16-89919746-G-A

Variant names:

• chr16-89919746-G-A
• rs885479
• NM_002386.4:c.488G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002386.4(MC1R):​c.488G>A​(p.Arg163Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0824 in 1,607,552 control chromosomes in the GnomAD database, including 19,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (2038 hom., cov: 33)
  • Exomes 𝑓: 0.082 (16986 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.07
• Publications: 263 publications found

Genes affected

MC1R (HGNC:6929): (melanocortin 1 receptor) This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.213233E-5).
• BP6: Variant 16-89919746-G-A is Benign according to our data. Variant chr16-89919746-G-A is described in ClinVar as Benign. ClinVar VariationId is 258652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.488G>A	p.Arg163Gln	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.488G>A	p.Arg163Gln	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.488G>A	p.Arg163Gln	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.488G>A	p.Arg163Gln	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes AF: 0.0913 AC: 13896 AN: 152166 Hom.: 2038 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0486

Gnomad OTH AF: 0.0788

GnomAD2 exomes AF: 0.152 AC: 37008 AN: 244212 AF XY: 0.135

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.0344

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0815 AC: 118637 AN: 1455268 Hom.: 16986 Cov.: 36 AF XY: 0.0786 AC XY: 56958 AN XY: 724254

African (AFR) AF: 0.0125 AC: 418 AN: 33468

American (AMR) AF: 0.377 AC: 16843 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0342 AC: 892 AN: 26112

East Asian (EAS) AF: 0.718 AC: 28515 AN: 39692

South Asian (SAS) AF: 0.0436 AC: 3758 AN: 86244

European-Finnish (FIN) AF: 0.213 AC: 10063 AN: 47184

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5768

European-Non Finnish (NFE) AF: 0.0475 AC: 52835 AN: 1111782

Other (OTH) AF: 0.0865 AC: 5216 AN: 60310

GnomAD4 genome AF: 0.0913 AC: 13896 AN: 152284 Hom.: 2038 Cov.: 33 AF XY: 0.105 AC XY: 7844 AN XY: 74440

African (AFR) AF: 0.0172 AC: 715 AN: 41578

American (AMR) AF: 0.234 AC: 3584 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.638 AC: 3291 AN: 5156

South Asian (SAS) AF: 0.0542 AC: 262 AN: 4834

European-Finnish (FIN) AF: 0.231 AC: 2453 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0486 AC: 3307 AN: 68012

Other (OTH) AF: 0.0775 AC: 164 AN: 2116

Alfa AF: 0.0657 Hom.: 2356

Bravo AF: 0.0957

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.0153 AC: 67

ESP6500EA AF: 0.0482 AC: 414

ExAC AF: 0.134 AC: 16230

Asia WGS AF: 0.293 AC: 1022 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Tyrosinase-positive oculocutaneous albinism;C1849452:SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.000032	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.16
Sift	Benign	0.035	D
Sift4G	Benign	0.30	T
Polyphen		0.0040	B
Vest4		0.052
MPC		0.017
ClinPred		0.0049	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs885479; hg19: chr16-89986154; COSMIC: COSV59624988; COSMIC: COSV59624988;